Cost-Effectiveness of Hydroxyurea for Sickle Cell Anemia in a Low-Income African Setting: A Model-Based Evaluation of Two Dosing Regimens.

BACKGROUND AND OBJECTIVE: The disease burden of sickle cell anemia (SCA) in sub-Saharan African (SSA) countries is substantial, with many children dying without an established diagnosis or proper treatment. The global burden of SCA is increasing each year, making therapeutic intervention a high priority. Hydroxyurea is the only disease-modifying therapy with proven feasibility and efficacy suitable for SSA; however, no one has quantified the health economic implications of its use. Therefore, from the perspective of the health care provider, we estimated the incremental cost-effectiveness of hydroxyurea as a fixed-dose regimen or maximum tolerated dose (MTD) regimen, versus SCA care without hydroxyurea. METHODS: We estimated the cost of providing outpatient treatment at a pediatric sickle cell clinic in Kampala, Uganda. These estimates were used in a discrete-event simulation model to project mean costs (2021 US$), disability-adjusted life years (DALYs), and consumption of blood products per patient (450 mL units), for patients between 9 months and 18 years of age. We calculated cost-effectiveness as the ratio of incremental costs over incremental DALYs averted, discounted at 3% annually. To test the robustness of our findings, and the impact of uncertainty, we conducted probabilistic and one-way sensitivity analyses, scenario analysis, and price threshold analyses. RESULTS: Hydroxyurea treatment averted an expected 1.37 DALYs and saved US$ 191 per patient if administered at the MTD, compared with SCA care without hydroxyurea. In comparison, hydroxyurea at a fixed dose averted 0.80 DALYs per patient at an incremental cost of US$ 2. The MTD strategy saved 11.2 (95% CI 11.1-11.4) units of blood per patient, compared with 9.1 (95% CI 9.0-9.2) units of blood per patient at the fixed-dose alternative. CONCLUSIONS: Hydroxyurea at MTD is likely to improve quality of life and reduce the consumption of blood products for children with SCA living in Uganda. Compared with a fixed dose regimen, treatment dosing at MTD is likely to be a cost-effective treatment for SCA, using realistic ranges of hydroxyurea costs that are relevant across SSA. Compared with no use of the drug, hydroxyurea could lead to substantial net savings per patient, while reducing the disease morbidity and mortality and increasing quality of life.

Assessment of Plasmodium falciparum Artemisinin Resistance Independent of kelch13 Polymorphisms and with Escalating Malaria in Bangladesh.

Emerging resistance to artemisinin drugs threatens the elimination of malaria. Resistance is widespread in South East Asia (SEA) and Myanmar. Neighboring Bangladesh, where 90% of infections occur in the Chittagong Hill Tracts (CHTs), lacks recent assessment. We undertook a prospective study in the sole district-level hospital in Bandarban, a CHT district with low population densities but 60% of reported malaria cases. Thirty patients presented with malaria in 2018. An increase to 68 patients in 2019 correlated with the district-level rise in malaria, rainfall, humidity, and temperature. Twenty-four patients (7 in 2018 and 17 in 2019) with uncomplicated Plasmodium falciparum monoinfection were assessed for clearing parasites after starting artemisinin combination therapy (ACT). The median (range) time to clear half of the initial parasites was 5.6 (1.5 to 9.6) h, with 20% of patients showing a median of 8 h. There was no correlation between parasite clearance and initial parasitemia, blood cell counts, or mutations of P. falciparum gene Pfkelch13 (the molecular marker of artemisinin resistance [AR]). The in vitro ring-stage survival assay (RSA) revealed one (of four) culture-adapted strains with a quantifiable resistance of 2.01% ± 0.1% (mean ± standard error of the mean [SEM]). Regression analyses of in vivo and in vitro measurements of the four CHT strains and WHO-validated K13 resistance mutations yielded good correlation (R2 = 0.7; ρ = 0.9, P < 0.005), strengthening evaluation of emerging AR with small sample sizes, a challenge in many low/moderate-prevalence sites. There is an urgent need to deploy multiple, complementary approaches to understand the evolutionary dynamics of the emergence of P. falciparum resistant to artemisinin derivatives in countries where malaria is endemic. IMPORTANCE Malaria elimination is a Millennium Development Goal. Artemisinins, fast-acting antimalarial drugs, have played a key role in malaria elimination. Emergence of artemisinin resistance threatens the global elimination of malaria. Over the last decade, advanced clinical and laboratory methods have documented its spread throughout South East Asia and Myanmar. Neighboring Bangladesh lies in the historical path of dissemination of antimalarial resistance to the rest of the world, yet it has not been evaluated by combinations of leading methods, particularly in the highland Chittagong Hill Tracts adjacent to Myanmar which contain >90% of malaria in Bangladesh. We show the first establishment of capacity to assess clinical artemisinin resistance directly in patients in the hilltops and laboratory adaptation of Bangladeshi parasite strains from a remote, sparsely populated malaria frontier that is responsive to climate. Our study also provides a generalized model for comprehensive monitoring of drug resistance for countries where malaria is endemic.

Effective use of hydroxyurea for sickle cell anemia in low-resource countries.

PURPOSE OF REVIEW: Over the past several decades, hydroxyurea has emerged as a well tolerated and potent disease-modifying therapy for children and adults with sickle cell anemia (SCA). Strong, evidence-based recommendations from the National Institutes of Health, American Society of Hematology, and British Society of Haematology document that hydroxyurea is now standard of care treatment for SCA. In low-resource settings, however, hydroxyurea is rarely utilized due to lack of availability, inadequate treatment guidance, and excessive costs. RECENT FINDINGS: Research trials conducted within the Caribbean and sub-Saharan Africa confirm the efficacy of hydroxyurea as a well tolerated, feasible, and beneficial treatment in low-resource countries. Hydroxyurea is therefore vital to reaching the targets for control of SCA outlined by the WHO. To maximize its utilization toward real-world effectiveness, specific attention must be given to healthcare provider education and training, public and institutional awareness, and medication access and affordability. SUMMARY: Efforts to introduce hydroxyurea effectively into low-resource countries should urgently address the lack of treatment guidelines, gaps in knowledge and clinical infrastructure, and medication inaccessibility. Partnerships among governmental, academic, pharmaceutical, and charitable organizations must tackle these barriers so that all individuals living with SCA worldwide can benefit from hydroxyurea.

Sickle cell disease: Translating clinical care to low-resource countries through international research collaborations.

The vast majority of the world's population of children and adults with sickle cell disease (SCD) are born in low-resource settings, particularly in sub-Saharan Africa, the Caribbean, the Middle East, and India. As a result numerous well-established, cost-effective, and evidence-based strategies for managing SCD such as newborn screening, early education, vaccinations, screening for stroke prevention, and treatments with safe transfusions and hydroxyurea are often unavailable, leading to substantial morbidity and increased mortality. Collaborations between high-income countries and these low-resource settings (North-South partnerships) have been advocated, with the goal of improving clinical care. Based on directives promulgated by the World Health Organization, we have developed a strategy of developing prospective research programs that focus on training, capacity building, and local data collection. This strategy involves consideration of important guiding principles, full partnerships, proper planning, and financial issues before program launch, after which rigorous program management is required for full effect and long-term sustainability. Ultimately these collaborative research programs should help create national guidelines and lead to improved clinical care for all children and adults with SCD.

Simultaneous point-of-care detection of anemia and sickle cell disease in Tanzania: the RAPID study.

Both anemia and sickle cell disease (SCD) are highly prevalent across sub-Saharan Africa, and limited resources exist to diagnose these conditions quickly and accurately. The development of simple, inexpensive, and accurate point-of-care (POC) assays represents an important advance for global hematology, one that could facilitate timely and life-saving medical interventions. In this prospective study, Robust Assays for Point-of-care Identification of Disease (RAPID), we simultaneously evaluated a POC immunoassay (Sickle SCAN™) to diagnose SCD and a first-generation POC color-based assay to detect anemia. Performed at Bugando Medical Center in Mwanza, Tanzania, RAPID tested 752 participants (age 1 day to 20 years) in four busy clinical locations. With minimally trained medical staff, the SCD POC assay diagnosed SCD with 98.1% sensitivity and 91.1% specificity. The hemoglobin POC assay had 83.2% sensitivity and 74.5% specificity for detection of severe anemia (Hb ≤ 7 g/dL). Interobserver agreement was excellent for both POC assays (r = 0.95-0.96). Results for the hemoglobin POC assay have informed the second-generation assay design to be more suitable for low-resource settings. RAPID provides practical feasibility data regarding two novel POC assays for the diagnosis of anemia and SCD in real-world field evaluations and documents the utility and potential impact of these POC assays for sub-Saharan Africa.

Sickle cell disease.

Sickle cell disease is a common and life-threatening haematological disorder that affects millions of people worldwide. Abnormal sickle-shaped erythrocytes disrupt blood flow in small vessels, and this vaso-occlusion leads to distal tissue ischaemia and inflammation, with symptoms defining the acute painful sickle-cell crisis. Repeated sickling and ongoing haemolytic anaemia, even when subclinical, lead to parenchymal injury and chronic organ damage, causing substantial morbidity and early mortality. Currently available treatments are limited to transfusions and hydroxycarbamide, although stem cell transplantation might be a potentially curative therapy. Several new therapeutic options are in development, including gene therapy and gene editing. Recent advances include systematic universal screening for stroke risk, improved management of iron overload using oral chelators and non-invasive MRI measurements, and point-of-care diagnostic devices. Controversies include the role of haemolysis in sickle cell disease pathophysiology, optimal management of pregnancy, and strategies to prevent cerebrovascular disease.

Characteristics of a rapid, point-of-care lateral flow immunoassay for the diagnosis of sickle cell disease.

Sickle cell disease (SCD) is a common and life-threatening hematological disorder, affecting approximately 400,000 newborns annually worldwide. Most SCD births occur in low-resource countries, particularly in sub-Saharan Africa, where limited access to accurate diagnostics results in early mortality. We evaluated a prototype immunoassay as a novel, rapid, and low-cost point-of-care (POC) diagnostic device (Sickle SCAN) designed to identify HbA, HbS, and HbC. A total of 139 blood samples were scored by three masked observers and compared to results using capillary zone electrophoresis. The sensitivity (98.3-100%) and specificity (92.5-100%) to detect the presence of HbA, HbS, and HbS were excellent. The test demonstrated 98.4% sensitivity and 98.6% specificity for the diagnosis of HbSS disease and 100% sensitivity and specificity for the diagnosis of HbSC disease. Most variant hemoglobins, including samples with high concentrations of HbF, did not interfere with the ability to detect HbS or HbC. Additionally, HbS and HbC were accurately detected at concentrations as low as 1-2%. Dried blood spot samples yielded clear positive bands, without loss of sensitivity or specificity, and devices stored at 37°C gave reliable results. These analyses indicate that the Sickle SCAN POC device is simple, rapid, and robust with high sensitivity and specificity for the detection of HbA, HbS, and HbC. The ability to obtain rapid and accurate results with both liquid blood and dried blood spots, including those with newborn high-HbF phenotypes, suggests that this POC device is suitable for large-scale screening and potentially for accurate diagnosis of SCD in limited resource settings.

A Cost-Effectiveness Analysis of a Pilot Neonatal Screening Program for Sickle Cell Anemia in the Republic of Angola.

OBJECTIVE: To assess the cost-effectiveness of a pilot newborn screening (NBS) and treatment program for sickle cell anemia (SCA) in Luanda, Angola. STUDY DESIGN: In July 2011, a pilot NBS and treatment program was implemented in Luanda, Angola. Infants identified with SCA were enrolled in a specialized SCA clinic in which they received preventive care and sickle cell education. In this analysis, the World Health Organization (WHO) and generalized cost-effectiveness analysis methods were used to estimate gross intervention costs of the NBS and treatment program. To determine healthy life-years (HLYs) gained by screening and treatment, we assumed NBS reduced mortality to that of the Angolan population during the first 5 years based upon WHO and Global Burden of Diseases Study 2010 estimates, but provided no significant survival benefit for children who survive through age 5 years. A secondary sensitivity analysis with more conservative estimates of mortality benefits also was performed. The costs of downstream medical costs, including acute care, were not included. RESULTS: Based upon the costs of screening 36,453 infants and treating the 236 infants with SCA followed after NBS in the pilot project, NBS and treatment program is projected to result in the gain of 452-1105 HLYs, depending upon the discounting rate and survival assumptions used. The corresponding estimated cost per HLY gained is $1380-$3565, less than the gross domestic product per capita in Angola. CONCLUSIONS: These data demonstrate that NBS and treatment for SCA appear to be highly cost-effective across all scenarios for Angola by the WHO criteria.

Hydroxyurea adherence and associated outcomes among Medicaid enrollees with sickle cell disease.

While laboratory and clinical benefits of hydroxyurea for patients with sickle cell disease (SCD) are well-established, few data describe the extent and implications of non-adherence. We sought to assess adherence to hydroxyurea among patients with SCD and investigate associations between adherence and clinical and economic outcomes. Insurance claims of North Carolina Medicaid enrollees (6/2000-8/2008) with SCD were analyzed. Inclusion criteria included age < 65 years, continuous Medicaid enrollment ≥ 12 months before and following hydroxyurea initiation, and ≥ 2 hydroxyurea prescriptions. Three hundred twelve patients, mean age 21 (± 12.2) years, met inclusion criteria and 35% were adherent, defined as a medication possession ration (MPR) ≥ 0.80; mean MPR was 0.60. In the 12 months following hydroxyurea initiation, adherence was associated with reduced risk of SCD-related hospitalization (hazard ratio [HR] = 0.65, p = .0351), all-cause and SCD-related emergency department visit (HR = 0.72, p = .0388; HR = 0.58, p =.0079, respectively), and vaso-occlusive event (HR = 0.66, p = .0130). Adherence was associated with reductions in health care costs such as all-cause and SCD-related inpatient (-$5,286, p < .0001; -$4,403, p < .0001, respectively), ancillary care (-$1,336, p < .0001; -$836, p < .0001, respectively), vaso-occlusive event-related (-$5,793, p < .0001), and total costs (-$6,529, p < .0001; -$5,329, p <.0001, respectively). Adherence to hydroxyurea among SCD patients appears suboptimal and better adherence is associated with improved clinical and economic outcomes.

Assessment of genotoxicity associated with hydroxyurea therapy in children with sickle cell anemia.

Hydroxyurea induces fetal hemoglobin, improves laboratory parameters, and ameliorates clinical complications of sickle cell anemia (SCA), but its long-term efficacy and safety in this patient population remain incompletely defined. Although generally considered non-DNA reactive, an important safety concern is that hydroxyurea may indirectly cause genotoxic damage. To better address this safety issue of hydroxyurea in patients with SCA, we measured the production of micronuclei (MN) in red blood cells (RBCs) as a marker of genotoxicity. Blood samples were collected from children with SCA enrolled in the Hydroxyurea Study of Long-term Effects (ClinicalTrials.gov NCT00305175). Flow cytometry quantified circulating MN-containing erythrocyte sub-populations before and during hydroxyurea exposure. The frequency of micronucleated reticulocytes (MN-CD71(+)) and micronucleated mature erythrocytes (MN-RBC) was then tested for associations with laboratory and clinical data. In cross-sectional analysis of 293 blood samples from 105 children with SCA and a median of 2 years of hydroxyurea therapy, exposure to hydroxyurea was associated with significantly increased frequencies of MN-CD71(+) and MN-RBC compared to baseline. The increases were evident by 3 months of therapy, and did not escalate further with up to 12 years of continuous drug exposure. In prospective longitudinal analysis, substantial inter-individual variation in the effect of hydroxyurea on %MN-CD71(+) was observed that was associated with the expected laboratory effects of hydroxyurea. In conclusion, clinically relevant exposure to hydroxyurea is associated with increased MN production consistent with erythroblast genotoxicity but with substantial inter-patient variability. Associations between increased %MN-CD71(+) and laboratory benefits suggest that hydroxyurea effects on MN production may be related to individual patient sensitivity to hydroxyurea within the bone marrow.